Abstract: The global epidemic of tuberculosis continues unabated. A particularly dangerous family of clinical strains is the "W-Beijing" family, many of which are highly drug resistant [MDR]. The substantial and relatively rapid transmission of these strains across the world has led people to believe that these particular isolates have some capacity or property to resist, and even subvert, the host immune response. Innovative work in the applicant's research group has uncovered the possibility that at least some of these isolates can induce Foxp3+ regulatory T cells that interfere with the proper expression of protective immunity in the mouse. Moreover, in the highly relevant guinea pig model, the applicant has published new flow cytometric technology to allow [for the very first time] the definition of the host pulmonary immune response. In this second model many of these W-Beijing strains cause extremely severe lung pathology, far worse than that seen using "laboratory strains" of Mycobacterium tuberculosis. This is a very important point, because all new vaccine candidates to date have only been tested against these laboratory strains. In this proposal we will use innovative new transgene mouse models to address the role of newly identified T cell subsets in modulating or subverting host immunity to this very serious group of pathogens, using our state of the art level III biosafety facilities. In addition, we will continue to develop innovative new methods to apply these studies to the [currently reagent-limited] guinea pig model. These studies will include three W-Beijing strains that cause a range [moderate to extremely severe] lung pathology [and for which we are submitting a proposal to the NIH to have these three undergo full genomic sequencing], and several characterized examples of drugsensitive/ drug-resistant genetically matched pairs to test the concept that acquisition of drug resistance reduces bacterial fitness, and hence virulence. Public Health Relevance: Tuberculosis is one of the most important diseases in the world. As recently emphasized by an NIAID document, virtually nothing is known about the host response to, and basic biology of, the rapidly spreading epidemic of MDR strains of this disease, and their potential subversion of these mechanisms. Such information is critical to rational vaccine design.